Autoregulation is the intrinsic tendency of the body to keep blood flow constant when blood pressure varies. In the brain, cerebral blood vessels are able to regulate the flow of blood through them by altering their diameters—they constrict when systemic blood pressure is raised and dilate when it is lowered. Cerebral blood flow autoregulation has been shown to be affected by a number of important clinical conditions such as premature birth, birth asphyxia, stroke, head injury, carotid artery disease, hypertension and vasovagal syncope. Acute cerebral diseases (e.g., traumatic brain injury, stroke) frequently lead to a rise in intracranial pressure (ICP) and impairment of cerebral autoregulation (see Aaslid R. et al., 1989, Cerebral autoregulation dynamics in humans, Stroke, 20:45-52; Czosnyka M. et al., 1997, Continuous assessment of the cerebral vasomotor reactivity in head injury, Neurosurgery, 41:11-19; Panerai R. B., 1998, Assessment of cerebral pressure autoregulation in humans-a review of measurement methods, Physiol. Meas., 19:305-338; and Schondorf R. et al., 2001, Dynamic cerebral autoregulation is preserved in neurally mediated syncope, J. Appl. Physiol., 91:2493-2502).
Assessment of cerebrovascular autoregulation state (CAS) could be of vital importance in ensuring the efficacy of therapeutic measures in the case of brain injury and stroke. Continuous monitoring of CAS and CAS monitoring data based treatment of intensive care patients with brain injuries or stroke will reduce mortality and morbidity of such patients.
Various methods have previously been introduced to assess CAS (see Aaslid R. et al. (1989), 20:45-52; Panerai R. B. (1998), 19:305-338). These discrete clinical tests, like the cuff leg test (see Aaslid R. et al. (1989), 20:45-52), however, did not provide continuous monitoring data about CAS. There is a need for continuous real-time CAS monitoring because it is the optimal monitoring for use with CAS based therapy.
A few methods and techniques have been proposed for invasive, semi non-invasive, and non-invasive monitoring of CAS (see Czosnyka M et al. (1997), 41:11-19; Schmidt B et al., 2003, Adaptive noninvasive assessment of intracranial pressure and cerebral autoregulation, Stroke, 43:84-89). These methods are based on the estimation of the correlation factor between arterial blood pressure (ABP) and ICP slow waves or ABP and cerebral blood flow velocity (CBFV) slow waves (see Czosnyka M et al. (1997), 41:11-19; Schmidt B et al. (2003), 43:84-89). In the case of intact cerebrovascular autoregulation, the correlation factor between ABP and ICP slow waves is negative and close to −1.0. In the case of impaired CAS the same factor is positive and close to +1.0.
The disadvantages of slow invasive or non-invasive ABP and ICP wave correlation monitoring methods include but are not limited to the following. First, slow ICP waves are not permanent and their amplitude is too low (less than 3.0 mmHg during main part of ICU patients' continuous monitoring time) to measure with sufficient accuracy. Also, non-invasive measurement or prediction of slow ICP waves adds additional errors and distortions of such waves. Further, if invasive slow ICP wave measurement is replaced by non-invasive transcranial Doppler (TCD) CBFV measurement, additional errors and distortions of such waves will occur. Moreover, slow ABP waves are also sometimes too small to measure with sufficient accuracy and non-invasively.
Also, the period of slow ICP or ABP waves is estimated to be from approximately 30 seconds to 120 seconds or more. In order to evaluate the CAS applying the intermittent slow wave method, it is necessary to accumulate the measured data during 4.0 minutes or longer. This is a relatively long time period and thus becomes a long term process. Long time period testing of CAS is not always effective because variability of CAS is a short-term process (see Panerai R B et al., 2003, Short-term variability of cerebral blood flow velocity responses to arterial blood pressure transients, Ultrasound in Med. & Biol., 29:1:31-38). Because of this time delay of prior art CAS monitoring systems, secondary brain injury can take place in ICU coma patients before the CAS monitoring data becomes available. The time delay of the slow wave CAS monitoring method is therefore too long for clinical practice of ICU patients monitoring and CAS based treatment.
Additionally, cerebrovascular autoregulation is a complex, nonlinear, and multivariate mechanism with considerable short-term variability (see Panerai R. B. et al. (2003), 29:1:31-38). A correlation factor can be applied without problems as an indicator of CAS only in linear autoregulatory systems. However, because the cerebrovascular autoregulation system is nonlinear (see Panerai R. B. et al., 1999, Linear and nonlinear analysis of human dynamic cerebral autoregulation, Am. J. Physiol., 277:1089-1099), any correlation factor between a reference signal (ABP slow wave) and a nonlinearly distorted cerebrovascular autoregulation system output signal (ICP or CBFV slow wave) would be a questionable indicator of CAS.
In our previous art (A. Ragauskas et al WO2006/050078), we presented a method for continuous real-time CAS monitoring based on simultaneous, non-invasive monitoring of intracranial blood volume respiratory waves (or other intracraniospinal characteristics related to the respiration processes) and lung volume respiratory waves (or other extracranial physiological characteristics related to the lung respiration processes). Intracranial blood volume respiratory waves and lung volume respiratory waves were filtered or decomposed in real-time into narrowband sinewave first harmonic components, and the phase shift between intracranial blood volume respiratory wave and lung volume respiratory wave first harmonics' was determined therefrom. Cerebrovascular autoregulation state (CAS) was derived from that phase shift value.
The method was based on the following assumptions:                If the phase difference between non-invasively measured intracranial blood volume respiratory waves and lung volume respiratory waves is close to zero, cerebrovascular autoregulation is impaired.        If the phase difference between intracranial blood volume respiratory waves and lung volume respiratory waves is equal or more than 30 to 40 degrees, cerebrovascular autoregulation is intact.        Phase difference reflects the severity of impairment of CAS. The smaller the phase difference, the greater the severity of impairment. The threshold value of 30 degrees divides the severity into intact CAS and impaired CAS.        
Similar results of phase shift dependence on frequency in the cases of intact CAS was obtained by M. Latka et. al (M. Latka, M. Turalska, M. Glaubic-Latka, W. Kolodziej, D. Latka, B. J. West, 2005, Phase dynamics in cerebral autoregulation, Am J Physiol Heart Circ Physiol, 289:2272-2279).
The disadvantages of the method described in WO2006/050078 to Ragauskas et al. are:                Sensitivity of the method is dependent on the frequency of the cerebral blood volume waves and respiratory waves. As shown in FIG. 7, this sensitivity decreases when frequency of respiration increases (see A. Ragauskas et al., 2005, Clinical study of continuous non-invasive cerebrovascular autoregulation monitoring in neurosurgical ICU, Acta Neurochir, Supp. 95:367-370).        In order to implement this method, it is necessary to use a respiratory sensor (lung volume sensor), which generates additional errors of phase shift. This error is dependent on the sensor's mounting position and patient respiration behavior.        
In the CAS evaluation methods which use ABP waves (slow waves or respiratory) it is necessary apply an invasive ABP sensor. Disadvantages of the use of invasive ABP sensor are:                implantation of ABP sensor in artery is a complex and risky procedure;        it necessary to replace ABP sensor periodically in order to avoid mortification of body parts; and        the use of invasive sensors is prohibitive of applying the method to healthy volunteers or to the patients with moderate or mild brain injuries or other brain pathologies not connected with injuries.        
Accordingly, it is an object of the present invention to provide a method and apparatus for continuous real-time CAS monitoring that solve the problems and cures the deficiencies of the prior art methods, apparatuses and techniques.
The present invention, which is a further development of the previous invention WO2006/050078 to Ragauskas et al., provides a non-invasive ultrasonic method and apparatus of CAS monitoring, which is based on the application of the following non-invasively monitored intracranial or cerebral blood volume (IBV) waves:                informative IBV slow waves, which phase shift due to human cerebrovascular autoregulatory mechanism has the highest sensitivity to CAS as shown in FIG. 7;        informative IBV respiratory waves, which phase shift due to human cerebrovascular autoregulatory mechanism also has sensitivity to CAS as shown in FIG. 7; and        reference pulse waves, which amplitude is modulated by intracranial slow and respiratory waves and which envelope contains slow waves and respiratory waves not affected by the cerebrovascular autoregulatory mechanism (CVA).        
We found experimentally during clinical studies of patients with traumatic brain injuries that the intracranial slow and respiratory waves extracted from the envelope of the intracranial pulse waves are not affected by human CVA. These waves are not informative, but they can be used as reference waves in comparison with informative slow and respiratory waves. Therefore, it is no longer necessary to use invasive or non-invasive extracranial ABP or respiratory wave sensors in order to get the reference waves for CVA status evaluation.
The phase shift between intracranial informative IBV slow waves and reference slow waves extracted from the IBV pulse wave envelope, as well as the phase shift between intracranial informative IBV respiratory waves and reference respiratory waves obtained from the pulse wave envelope give information about the human CAS. The simultaneous application of intracranial blood volume waves obtained from wide frequency range (respiratory waves and slow waves) allows us to increase the reliability of the real-time monitoring information about human CAS status.